Journal of Lipid Research
Volume 53, Issue 2, February 2012, Pages 300-310
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Research Articles
Diabetes-induced myelin abnormalities are associated with an altered lipid pattern: protective effects of LXR activation

https://doi.org/10.1194/jlr.M021188Get rights and content
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Diabetic peripheral neuropathy (DPN) is characterized by myelin abnormalities; however, the molecular mechanisms underlying such deficits remain obscure. To uncover the effects of diabetes on myelin alterations, we have analyzed myelin composition. In a streptozotocin-treated rat model of diabetic neuropathy, analysis of sciatic nerve myelin lipids revealed that diabetes alters myelin's phospholipid, FA, and cholesterol content in a pattern that can modify membrane fluidity. Reduced expression of relevant genes in the FA biosynthetic pathway and decreased levels of the transcriptionally active form of the lipogenic factor sterol-regulatory element binding factor-1c (SREBF-1c) were found in diabetic sciatic nerve. Expression of myelin's major protein, myelin protein zero (P0), was also suppressed by diabetes. In addition, we confirmed that diabetes induces sciatic nerve myelin abnormalities, primarily infoldings that have previously been associated with altered membrane fluidity. In a diabetic setting, synthetic activator of the nuclear receptor liver X receptor (LXR) increased SREBF-1c function and restored myelin lipid species and P0 expression levels to normal. These LXR-modulated improvements were associated with restored myelin structure in sciatic nerve and enhanced performance in functional tests such as thermal nociceptive threshold and nerve conduction velocity. These findings demonstrate an important role for the LXR-SREBF-1c axis in protection from diabetes-induced myelin abnormalities.

diabetic neuropathy
liver X receptor
myelin composition
peripheral nerve
sterol-regulatory element binding factor-1c
fatty acid synthesis

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This work was supported by a Giovanni Armenise-Harvard Foundation Career Development Grant (NM).

The online version of this article (available at http://www.jlr.org) contains supplementary data in the form of four figures.

    Abbreviations:

    DPN

    diabetic peripheral neuropathy

    GSL

    glycosphingolipid

    IS

    internal standard

    LXR

    liver X receptor

    P0

    myelin protein zero

    PC

    phosphatidyl choline

    PE

    phosphatidyl ethanolamine

    PI

    phosphatidyl inositol

    PMP22

    peripheral myelin protein 22

    PS

    phosphatidyl serine

    SCD-1

    stearoyl-CoA desaturase-1

    SCD-2

    stearoyl-CoA desaturase-2

    SM

    sphingomyelin

    SREBF-1c

    sterol-regulatory element binding factor-1c

    STZ

    streptozotocin

    Sulf

    sulphatides

    TEM

    transmission electron microscopy

1

G. Cermenati and F. Abbiati contributed equally to this work.